IL193283A - Drug delivery system and method of manufacturing it - Google Patents
Drug delivery system and method of manufacturing itInfo
- Publication number
- IL193283A IL193283A IL193283A IL19328308A IL193283A IL 193283 A IL193283 A IL 193283A IL 193283 A IL193283 A IL 193283A IL 19328308 A IL19328308 A IL 19328308A IL 193283 A IL193283 A IL 193283A
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- IL
- Israel
- Prior art keywords
- drug
- layer
- deposited
- additional
- adhered
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/12—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- C—CHEMISTRY; METALLURGY
- C23—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
- C23C—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
- C23C14/00—Coating by vacuum evaporation, by sputtering or by ion implantation of the coating forming material
- C23C14/02—Pretreatment of the material to be coated
- C23C14/021—Cleaning or etching treatments
- C23C14/022—Cleaning or etching treatments by means of bombardment with energetic particles or radiation
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- C—CHEMISTRY; METALLURGY
- C23—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
- C23C—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
- C23C14/00—Coating by vacuum evaporation, by sputtering or by ion implantation of the coating forming material
- C23C14/22—Coating by vacuum evaporation, by sputtering or by ion implantation of the coating forming material characterised by the process of coating
- C23C14/221—Ion beam deposition
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- C—CHEMISTRY; METALLURGY
- C23—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
- C23C—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
- C23C14/00—Coating by vacuum evaporation, by sputtering or by ion implantation of the coating forming material
- C23C14/22—Coating by vacuum evaporation, by sputtering or by ion implantation of the coating forming material characterised by the process of coating
- C23C14/50—Substrate holders
- C23C14/505—Substrate holders for rotation of the substrates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
- A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
- A61F2250/0067—Means for introducing or releasing pharmaceutical products into the body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
- A61L2300/406—Antibiotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/42—Anti-thrombotic agents, anticoagulants, anti-platelet agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/426—Immunomodulating agents, i.e. cytokines, interleukins, interferons
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/606—Coatings
- A61L2300/608—Coatings having two or more layers
- A61L2300/61—Coatings having two or more layers containing two or more active agents in different layers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/18—Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment
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- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
- H01J2237/00—Discharge tubes exposing object to beam, e.g. for analysis treatment, etching, imaging
- H01J2237/06—Sources
- H01J2237/08—Ion sources
- H01J2237/0812—Ionized cluster beam [ICB] sources
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/249921—Web or sheet containing structurally defined element or component
- Y10T428/249953—Composite having voids in a component [e.g., porous, cellular, etc.]
- Y10T428/249987—With nonvoid component of specified composition
- Y10T428/249988—Of about the same composition as, and adjacent to, the void-containing component
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/31504—Composite [nonstructural laminate]
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Materials Engineering (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Mechanical Engineering (AREA)
- Metallurgy (AREA)
- Vascular Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Surgery (AREA)
- Epidemiology (AREA)
- Transplantation (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Cardiology (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Composite Materials (AREA)
- Obesity (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Materials For Medical Uses (AREA)
- Media Introduction/Drainage Providing Device (AREA)
- Prostheses (AREA)
Abstract
In one embodiment, a drug delivery system and method provide a member including a combination of a drug substance and a polymer or other material, and an encapsulating layer formed in an outer surface of the member by gas cluster ion beam irradiation of the outer surface of the member, which encapsulating layer is adapted to determine one or more characteristics of the drug delivery system.
Description
DRUG DELIVERY SYSTEM AND METHOD OF MA ING THEREOF EXOGENES1S CORPORATION WO 2 I DRUG DELIVERY SYSTEM AND METHOD OF MANUFACTURING THEREOF Field of the I nvention This invention relates general ly to drug delivery systems such for medical devices implantable in a mammal coronary and specifically to a method and for applying and adhering drugs to the surface of medical devices and for control the surface characteristics of such drug del ivery systems such for the drug release rale and using gas cluster ion beam technology in a manner that permits efficacious release of the drugs from the surface over Background of the inven tion coronary stent is an implantable medical device that is used in combination with balloon Balloon angioplasty is a procedure used to treat coronary loon angioplasty compresses plaque the walls of the blocked artery by the inflation of a balioon at the tip of a catheter inserted into the artery during the angio lasty the response to this procedure often includes thrombosis or blood and the of scar tissue or other tissue reactions at the treatment Statistics show that restenosis or narrowing of the artery by scar tissue after bal loon angioplasty occurs in up to 35 percent of treated patients within only six months these leading to severe complications in many To reduce cardiologists are now often placing small tubular dev ices of various such as wire expandable metal and and biodegradable polymers cal a coronary stent at site of blockage during balloon The goal is to the stent act as a scaffold to keep the coronary artery open alter the removal of the there arc also serious compl ications associated with the use of coronary Coronary restenotic complications associated with stents occur in 16 to 22 percent WO of cases in six after of the stent and are believed to be caused by many factors acting alone or in These complications could be reduced by several types of drugs introduced local ly at the site of stent Because of the substantial financial costs associated with treating the complications of such as intensive a reduction in restenosis rates would save money and reduce patient Numerous studies suggest that the current popular designs of coronary are functionally Although the use of coronary stents is the benefits of their use remain controversial in certain clinical situations or indications due to their potential It is widely held that during the process of expanding the damage occurs to the endothelial lining of the blood vessel triggering a heating response that the To help combat that stents are being introduced to the market to help control the abnormal cell growth associated with this healing These drugs are typically mixed with a l iquid polymer and applied to the stent When the drug elutes out thc polymer in releasing the medicine into the surrounding There remain a number problems associated with this Because the stent is expanded at the diseased the polymeric material has a tendency to and sometimes from the stent These polymer can travel throughout the system and cause signi ficant There is some evidence to suggest that the polymers themselves cause a toxic reaction in the because of thickness o coating necessary to carry the required of the stents can become somewhat rigid making expansion di other prior art the wire mesh of thc stent itsel f is impregnated with one or more drugs through processes such as high pressure and spraying and dipping do not satisfactorily adhere drug to the stent surface and in many do yield the dosage of the drugs delivered to the surrounding The polymer coaling can include several layers such as the above drug containing layer as well as a drug free encapsulating which can help to reduce init ial drug release amount caused by initial exposure to liqu ids when the device is first A further base coating polymer located beneath the drug bearing layer is also One example of arrangement used on steel stents includes a base layer of and mixture WO includ ing acetate and poly melhacrylate in a two to one along with an impregnated top layer of the same mixture of The drug used is a relatively new immunosuppressant drug also known us Several other combinations exist from several In view of this new approach to in drug it is desirable to greater control over the drug release rate from the implantable device us well as control over other surface characteristics of the drug delivery It is therefore an object of this invention to provide a means of applying and adhering drugs to medical devices gas cluster beam It is a further object of this invention to apply drugs to medical stents by gas cluster ion beams to decrease the complication of restenosis and It is a further object of this invention to provide a means for control surface characteristics of a drug cluting material using gas cluster ion beam It is n further object o f this invention to transform the surfaces of medical devices into drug del ivery systems by applying and adhering drugs to the surfaces with gas cluster ion beams so as to facilitate a timed release of from the It is a further object of this invention to improve the functional of known in said to drug release mechanisms using gas cluster beam Summary of the Invention The objects set forth above as as further and other objects and advantages of the present invention are achieved by the described herein The present invention is directed to the use of gas cluster surface modification to or adhere various drug molecules directly into or onto the surface of a stent or other medical thereby eliminating the need for a polymer or any other binding agent and transforming the device surface into a drug delivery Th is wil l prevent the problem of toxicity and the damage caused by transportation of delaminatcd polymeric material throughout the Unlike the prior art stents described above that load the stent material the invention provides the WO l 787 ability to for an optimal dosage of the drug or The appl ication of the is achieved through the use of The application of is accomplished by several The surface of the medical which be for of a metal or any other is optionally first processed using a GO which will remove any oxide layers from the surface rendering the surface electrically active and creating dangling The desired drug will then be deposited upon the active surface and will bond with the dangling Λ second method for a drug delivery system involves depositing a layer of one or more drug substances onto at least one surface region of a medical device may or may not have with a in powder or other perhaps through sublimating the and then impacting the deposited drug layer with an energetic GCIB so as to form an adhered drug The dose a carbonized drug matrix a plurality through which drug wil l diffuse or over deposited drug layer is suitably some GCIB cl usters may penetrate through the deposited drug layer and reach the surface of the medical suc that adhered drug layer may include some portion of the deposited drug molecules implanted in the form of a mechanical the deposited drug layer has a thickness above a threshold thickness a particular GCIB the carbonized drug will be to the surface of medical the carbonized matrix will be formed over the remaining mobile volume of the deposited In one stent for a carbonized drug matrix is formed concentrically about a layer of deposited drug in is disposed about the stent on the stent with little to no port ion of the carbonized matrix d irectly stitched to the stent In embodiments of the subsequent drug layers may be comprised of similar or distinct drug similar or different drug deposition techniques than those used to deposit preceding layers may be Controlled variations in the GCJ characteristics dosing delivered to di ferent layers between spatial inct regions of a single may also be Substantially simi lar doses del ivered to substantial ly similar drug substances wilt result in similar drug elution while different doses can achieve WO 5 distinct Judicious selection of drug and control over the deposition techn and dosing permits formation of drug delivery system comprised of mu adhered drug each having similar or differing drug eiution profiles in preferred iments of cooperate to achieve at least overall drug eiut ion the eiution les of individual layers may be designed such as drug is diffused from the outermost adhered drug it is replenished by eluting from lower adhered Λ number of techniques may be employed to deposit the drug the medical device or one or more spatially distinct regions If the drug is to be deposited in liquid iques such as vapor phase and ultrasonic may be if the drug is powder it may be electrostatically deposited onto the medical device surface or deposited by and then irradiated in the same manner described Any of the methods described may optional ly include an irradiation step prior to drug deposition to obtain a smoother which will help reduce thickness in the adhered drug The application via surface modi fication such as described above will reduce compl lead to genuine cost savings improvement patient quality li and overcome prior problems of thrombosis and Preferred therapeutic agents for delivery in the drug delivery systems of the present invention include immunosuppressant cholesterol reducing medications and combinations Jn one a drug delivery comprises a member including a combination of a drug substance and a polymer or other and an encapsulating layer formed in an outer surface of the member by gas cluster ion beam irradiation of the outer surface of the which encapsulating layer is adapted to determ ine a release rale for the drug from the The encapsulating layer may include a plurality of openings located at an outer surface of the encapsulating layer and adapted to permit amounts of the drug substance to be released from the member at a rale determined by the encapsulating VVO 6 encapsulating layer may include a carbonized or densified The encapsulating layer may be to i a measure of biocompatibil ily of the member may be located on a surface of a medical The drug substance may be selected from the group of i cholesterol reducing agents and combinal ions Λ medical device may inc lude the drug delivery described In another a drug del ivery system comprises a cohesive mixture including a combination drug and a polymer or other and a carbon ized or densi lied matrix formed on an outer surface of the cohesive which carbonized or densified matrix is adapted to determine a release rale for the drug substance from the cohesive In yet another a method for producing a drug delivery comprises steps of provid ing a member including a combination of a drug substance and a polymer or other and irradiating on outer surface of the member with a gas cluster beam to determ a release rate for the drug substance from the The step of providing a member may include forming cohesive mixture of the drug substance the polymer or other material on a surface of a medical The step of irradiating may include form ing an encaps lating at least an external surface of the which encapsulating is adapted to control release of the drug substance from the The encapsu layer may include a plurality of openings at an outer surface of the encapsulating Iayer as to permit portions of the drug substance to be released from the member at a rate determined by the encapsulating The encapsulating Iayer may include a carbonized or densified of providi g may include the steps of providing a polymer element and adhering a drug substance to outer surface of polymer The step of providing a polymer element may include step of irradiating the outer surface o polymer element with a gas cluster ion beam prior lo the step of The step of irradiating may be adapted to lower in situ chemical reactivity of external surface of the cohesive The drug substance may selected from the group consisting of WO 7 cholesterol reducing agents and combinations Brief Description of Drawings For a understanding of the present with uther and further objects reference is made to the accompanying is a schematic view of a gas cluster ion beam processing system used for practicing the method present 2 is an exploded view a portion gas cluster ion beam processing system of 1 showing the workpiece 3 is an atomic force microscope image showing the surface of a coronary stunt before GCI is an atomic force microscope image showing surface of a coronary alter illustrations of a surface region of a medical device at various stages of drug delivery system formation in accordance with an embodiment of the present are illustrations of alternative drug delivery structure embodiments in accordance with he present 7A is a graph showing the release rate of fluorescence over 7B is a graph showing the cumulative release rate of fluorescence over 8 is a graph showing comparative drug rate test results for a conventional stent and stent processed in accordance with the present 9 is a cross section of a drug delivery system prior to processing in accordance with another embodiment of the present and is cross section of the drug delivery system of 9 shown during gas cluster ion beam processing performed in accordance with the present WO 8 Detailed Descriptio of the Drawings Beams o f energetic electrically charged atoms or molecules accelerated through high voltages under are widely utilized to form semiconductor device to smooth surfaces by and to the properties of semiconductor thin In the present these same beams o energetic ions are util ized for the applying and adhering drugs to a surface and for affecting surface characteristics of drug cluting medical such for coronary thereby converting the surface into a drug delivery system with enhanced drug delivery properties and In the preferred embodiment of the present gas cluster ion processing is uti Gas cluster ions are formed from large numbers of weakly bound atoms or molecu les sharing common electrical charges and accelerated together through h igh voltages to have high total Cluster ions disintegrate upon the total energy of the ckister is shared among the constituent Because of this energy the atoms arc individual ly much less energetic than the case of conventional ions or ions not clustered together as a the atoms penetrate to shorter Surface sputtering are orders of magnitude stronger than corresponding effects produced by conventional thereby making important microscale surface effects possible that are not possible in any other The concept of processing has only emerged over the past Using a GCIB for dry and smoothing of materials is in the art and has been for by in Surface Treatment Method Because ionized clusters containing on the order of thousands of gas atoms or molecules may be formed and accelerated to modest energies on the order of a few thousands of electron individual atoms or molecu les in the clusters may each only have an average energy on the order of a few electron is the teachings of for that such individual atoms are not energetic enough to signi icantly penetrate a surface to cause residual damage typically associated with plasma po the clusters themselves arc sufficiently energetic thousands of electron to effectively or clean WO y Decausc the individual atoms within a gas cluster ion are very a few the atoms penetrate through only a atomic of a target surface during shallow of the impacting atoms all of the energy by the entire cluster ion is consequently dissipated in an extremely l volume in the top surface layer during a period on the order of l seconds one This is different from the case of implantation which is normal done with conventional monomer ions and where the is to penetrate into the sometimes penetrating several thousand to produce changes in the surface properties of the Because of the high total energy of the cluster ion and extremely small interaction the deposited energy density ut the impact site is far greater than in the case of bombardment by conventional monomer Reference is now made to 1 of the drawings which shows the processor of invention utilized for applying or adhering drugs to the surface of a medical device such coronary stent Although not limited to the specific components described the processor 100 is made up of a vacuum vessel which is divided into three communicating a source chamber an chamber and a processing chamber which includes therein a un iquely designed holder capable of positioning the medical device uniform and drug application by a gas cluster ion During the processing method of this the three chambers arc evacuated to suitable operating pressures by vacuum pumping and Λ condensable source gas 12 example argon or stored in a cyl inder I 1 1 is admitted pressure through gas metering valve 1 and gas feed lube into stagnation chamber i and is into the substantially lower pressure vacuum through a properly shaped nozzle resulting in a supersonic gas jet I 1 which results from the in the causes a portion of the gas jet to condense into each consisting of from several lo several thousand weakly bound atoms or molecu Λ skimmer aperture 120 partially separates the gas molecules that have not condensed into cluster rom the c luster jet so as to minimize pressure in the downstream regions where such higher pressures wou ld be detrimental ion izer high voltage electrodes and process chamber Suitable condensable source gases 1 but not necessarily limited lo carbon WO 787 10 After the superson ic jet 1 containing gas clusters has been the clusters are ionized in an ionizer The 122 is typical ly an electron impact ionizer that produces from one or more incandescent filaments and accelerates and directs the causing to collide with the gas clusters the gas jet 1 where the jet pusses through the ionizer The electron impact ejects electrons From the causing a portion the clusters to become positively A set of suitably biased high voltage electrodes 1 extracts the cluster ions from the ionizer forming a Ihcn accelerates the cluster ions to a desired energy from I keV to several of and focuses them to form a GC1B having an initial trajectory Filament power supply 1 36 provides voltage heat the ionizer Anode power supply provides voltage to uccclerate emitted from filament to cause th m to bombard the cluster con taining gas jet 1 8 to produce Extraction power supply provides voltage to bias a high voltage electrode lo extract from the ionizing region of ionizer 122 and to form a GCI Accelerator power supply provides voltage bias a high voltage electrode with respect to the ionizer 122 so as to resu lt in a total GCIB acceleration energy equal to electron volts more power supplies 142 and for may provided to bias high voltage electrodes with potentials and for to focus the GCIB A medical such as coronary stent to be processed by the GCIB processor is held on a workpiece holder 1 and disposed in the path of the GCIB for The present invention may be utilized with medical devices composed of a variety of such as or combinations In order for the stent to be uniformly processed using GCI the workpiece holder 1 is designed in a manner set forth below to manipulate the stent in a specific Referring now 2 of the medical device surfaces that are such as those of must remain oriented within specific angle tolerance with respect the normal beam incidence lo obtain paramount effect to the stent surfaces utilizing This requires a fixture or workpiece holder with the ability to be fully articulated to orient all surfaces of stent to be modified with in that specific angle tolerance at a constant exposure level for process optimization and uni Any stent containing surfaces lhat would be exposed lo the process of greater wo 1 from normal incidence may require More speci when applying to a coronary stent workpiece holder is rotated and articulated by a mechanism located at t e end of the GCIB processor The mechanism preferably permits 360 degrees of device rotation about longitudinal axis and sufficient device articulation about an axis perpendicular to axis 4 to maintain the to within degrees from normal beam Referring back to I under certain depending upon the size o lhe coronary stent a scanning system may be desirable to produce Although not necessary for two pairs of orthogonally oriented electrostatic plates and may be utilized to produce a raster or other scanning pattern over an extended processing When such beam scanning Is a scan generator provides arid scanning signal voltages to the pairs of scan plates 130 and 132 through lead pairs and 1 The scanning signal vo ltages are commonly triangular waves of different frequencies that cause the GCIB 128 to be converted into a scanned GCIB which scans the entire surface of the stent Additional means for orient articulating rotating devices such as stents and orthopedic products arc disclosed Patent 1 to el to ei and lo el the contents of each which hereby incorporated by When beam scanning over an extended region is not processing is generally confined to a region that is by diameter of the The diameter of the beam at the surface can be set by selecting voltages of one or more lens power supplies 1 2 and shown for to provide the desired beam diameter at the I one processing step related to the present the surface of a medical device is irradiated with a prior to the deposition of any substance on the surface This will remove any contaminants and oxide layers from the stent surface rendering the surface electrically active and capable of attracting and bonding drug and polymer molecules that are then introduced to the One or tnore types of drugs are deposited upon surface through vapor phase deposition or by introducing a liquid form of drug onto the In some the l iquid form of the drug is in solution with WO 12 a volatile solvent requiring the solvent to be As the formed mechanical bonds arc over the drug is slowly released to the site of device Studies suggested that a wide variety of drugs may be useful at the site of contact the medical device and the in vivo envi For drugs such as thrombotic and cholesterol reducing agents may reduce instances of restenosis when diffused into the blood vessel wall alter insertion of In another processing processing is utilized to impact a deposited drug layer the surface of the medical device if the deposited drug layer is th in enough to permit gas clusters penetration to the with energetic clusters thus implanting and forming a mechanical bond between the surface and the deposited drug or to implant the drug molecules of the electrostatically or sublimated medicine in powder form to the stent surface in the same manner described The impact energy of gas clusters causes a portion of the deposited drug molecules to form a carbonized drug As the carbon matrix is remaining drug molecules become embedded within the interstices of the arc encapsulated betwee the matrix and the medical device Over these drug molecules diffuse through the matrix and are released at the contact site between the stent and the blood vessel wall thereby continuously providing medication to As the atom ic force microscope images shown in 3 and 4 it is possible to dramatically affect the med ical device surface utilizing gas cluster ion 3 shows a stent surface before GC1 treatment with gross surface on strut The surface roughness measured of 3 angstroms and an of irregularities highl ight the condition at the cellu lar level where thrombosis 4 shows stent surface alter processing where the surface has been eliminated without any measurable physical or structural change to the integrity of the stent itsel The surface roughness measured an angstroms and an 25 In this GCH3 processing also provides the added benefit of smoothing the surface of the medical surfaces may snare and other matter WO PC 13 f urther With reference to a method of producing a drug delivery systcrti will now be 5Λ illustrates a surface region of a medical device such for stent 1 has been positioned in a vacuum chamber such that it can be irradiated with gas clusters of a as would occur in an optional smoothing process i l lustrates drug del i very structure in accordance with an embodiment of the present Note that the drug delivery structure may cover ail or less than the entirety of the exterior surface of stent in the latter surface region 12 represents but one of a plural ity of spatially distinct surface regions 14 o f stent upon which the drug delivery system is Each of the distinct surface regions 1 may the same or similar type of or completely d istinct types of For ease in the description that follows focuses on the of the drug delivery structure at surface region illustrates surface region as being relatively fol lowing an optional surface preparation step through GCI B As described such processing removes contaminants and electrical activates the surface region 5C shows a drug layer which may be deposited by any of the techniques described and which preferably has been deposited to a substantially uniform thickness in the vicinity of region A drug is used herein to refer to a contiguous drug layer deposited over the entirety of the surface of the medical such as deposited drug layer or alternatively may be used in a collective sense to refer to numerous spatially distinct deposits of the same or different therapeutic agents on the surlace ither deposited drug layer is GCIB irradiated to form an adhered drug layer on the device surface from which a portion of the deposited agent l be released over time to a tissue adj the medical As the is used an drug refers collectively to the GCI irradiated layer comprised of at least one portion of deposited drug and at least one carbonized matrix through which the deposited drug is released at an expected In embodiments described a drug delivery system comprised of adhered drug layers may subsequently be formed by repeatedly depositing additional layers of a selected drug substance onto a preceding adhered layer and the additional deposited drug layer with The 1 with subsequent layer and the surface o f the medical such layers will be adhered to preceding drug matrix And in certain the carbonized drug matrix of even the first layer will be or to the stent i l lustrates the step of irradiating the first deposited drug layer with GCIB gas clusters 1 This results in the formation of a first adhered drug layer which is comprised of two primary such as shown in First adhered drug layer and subsequently formed adhered drug each include a carbonized drug matrix 20 having a plurality of interstices 22 in which be disposed the remainder o f the deposited drug that was not carbonized by the Drug layer is adhered to the surface region 1 and a portion of the drug will be released at an expected rale as an elution from the adhered drug layer 1 by diffusion through the interstices 22 of the carbonized drug matrix A number of the interstices 22 are and a portion of the interstices are open at each surface of the drug matrix so as to permit drug to eventually elute from a substantial number of the interstices 22 of the drug matrix illustrate how the drug deposition GCIB irradiation process steps may be to achieve drug delivery structures having variable and extremely accurate drug More F illustrates a second drug layer 24 deposited upon the first adhered drug layer 1 using the same or an alternative deposition The second drug layer 24 is then irradiated with GC IB gas clusters 26 delivering substantial ly similar dosing or di depending upon desired el ution Similar GC IB irradiation doses delivered to substantially similar or identical therapeutic agents wil result in substantially similar elution profiles between or among adhered illustrates a drug delivery system comprised of an adhered drug layer 28 that is further comprised of the first adhered drug layer and a second adhered drug layer As many repetitions of the drug deposition irradiation steps as needed to attain an overall elut ion or profiles multiple therapeutic agents are uti l may be In one preferred the first adhered drug layer and second adhered drug layer 30 are simi larly formed to have simi lar elution such as drug is released from the interstices 32 f layer drug eluting from layer into layer 30 replenishes the released The adhered drug layers 30 are not comprised of the drug Several alternative drug delivery systems in accordance with the present invention WO 15 agents are uti be In one preferred embod first adhered drug layer and second adhered drug layer 30 arc similarly formed to have ilar such as drug is released from interstices 32 of laycr drug from layer into layer 30 replenishes the released adhered drug layers 30 are necessari comprised of the same drug Several alternative drug delivery systems in accordance with the present invention will now be with reference to As multiple including the thickness of the deposited drug will determine whether OCIB gas clusters will penetrate a deposited drug layer so as to reach the which a drug layer is to be 6A 5 illustrates a drug delivery system that is further of spatially distinct adhered drug structures when GC I gas clusters penetrate a thinly deposited drug layer on the order of several to tens of or Note that some portion adhered drug structures are bonded to spatially distinct surface regions Formation of each of the adhered drug structures be nearly simultaneously or in separate processing The therapeutic to be released from of the adhered drug structures is deposited at the associated spatially distinct surface region 14 and then GC1 I3 the drug deposited at each surface region is not necessarily the Forming adhered drug structures on less than the entire surface of the medical device has the benefit of cost savings when an expensive drug is to be certain drugs may only need to be delivered at particular such as at a site of significant tissue interaction with an implanted medical 613 illustrates an alternative embodiment of a drug delivery such as may be formed when GC1 B does not penetrate the thickness of a drug layer deposited on the surface region 12 of the medical device In such a carbonized drug matrix 22 is still formed having with in which some portion of carbonized drug is and from which drug is however the drug matrix 22 docs not extend to the surface 12 of the medical device the carbonized matrix 22 encapsulates the remainder of deposited drug 24 that was not carbonized by the captured in the between the drug 22 and the surface 1 uf the device As noted the expression drug VVO 16 us refers Collectively to the and the of deposited whether disposed in the interstices or encapsulated by drug matrix 22 and the device Now turning to 7Λ and elution rates for a substance adhered to a surface of a coronary stent using processing in accordance with one embodiment of the present is To demonstrate the release of a molecule adhered to the surface in accordance with present the surface was irradiated and a organic dye was vapor deposited onto the freshly irradiated surface while the surface remained in the The dye elution rate was measured by observing the of the as a function of 7 the release rate is shown over In the cumulative release rate is shown over 8 illustrates results of comparati elution rate performed on a conventional sletu and a upon which an exemplary drug delivery system has been firmed utilizing irradiation in accordance with the present was selected as the tesl which in the case of the processed was and for the processed stent was deposi by ultrasonic prior to being irradiated an Argo GCIB whi rotating the between RP The itaxol was allowed to from the respective stents over time into a Bovine Serum Buffered Saline and the drug remaining on the stents was As significantly more drug remained loaded on the stent for a longer period o that the conventional drug coated stent With reference to a drug delivery system i which includes a drug containing medium and an optional substrate or med ical device 1 is shown prior to processing by t e method of the present Medical device is only representational and may lake any suitable Device 1 may include an implantable medical device such us a stent or any other medical device which may benefit from an in situ drug delivery the use of substrate or device may be limited fabrication of drug containing med ium wherein subslrale or device 14 is removed from medium prior to Substrate or device 1 maybe constructed of any suitable material such for ceramic or a of or device may also be surface treated using in accordance with the method mentioned prior to the application of medium WO J7 Drug containing medium may take any suitable such as the various arrangements discussed Medium 1 may just a single layer of drug containing or it may include multiple layers 1 as described Although the existing art identifies the of an outer layer to control initial drug the process of the present invention may be used with this known to further control surface characteristics of the including the drug release rate alter initial in situ liquid Drug medium may be applied to device 14 in any suitable arrangement from a portion to complete or almost complete enclosure of device 1 One method of application of medium 1 to device uses a drug polymer mixture with a volatile which is deposited upon surface of device The solvent is evaporated to leave a cohesive mixture in the form of medium attached to the Once the solvent is drug medium 12 may form cohesive or mass thereby provide a suitable drug delivery even in the absence of device With reference to the delivery system 1 is shown undergoing irradiation with a gas cluster ion Λ stream 130 of gas cluster molecules is being scanned across section of drug delivery device 1 The clusters 132 break up upon impact with the surface 134 resulting in the shallow implantation of individual or small groups of molecules Most of the individual molecules 136 stop within the first couple of molecular levels of 1 with the result that most of a thin layer 138 at surface 134 is densillcd or carbonized by the impinging The scaling is not as various openings remain in surface which openings ultow for the elution of drugs from medium it is through the amount of irradiation that characteristics of surface are The greater the amount οΓ the fewer and smaller are the openings in surface thereby slowing the release of drugs from medium this or carbonization 134 causes pacification or sealing of surface which can decrease the of surface 134 contact with living In the case of some materials which may be used for medi 1 densifieation or carbonization can limit the release of volatile organic compounds by the medium into surrounding living process of the present invention enhances the choices of materials which may be used to WO 18 construct medium and can reduce risk factors associated with those material Studies ave suggested that a wide variety of drugs may be useful at the site of contact between the medical device and the in situ For drugs such as 5 thrombotic and cholesterol reducing agents may reduce instances of restenosis when diffused into the vessel wall after insertion of the Although the present invention is described in reference to its applications and the hereof are not limited to stents include any contact with a living body where drug delivery may be Although the invention has been described with respect to various it should be realized this invention Is also capable of a wide variety of further and other embodiments within the spirit and scope of the appended insufficientOCRQuality
Claims (2)
1. . . . . _ medical device so as to form a first deposited drug layer; (cj_ orming a first gas cl uster ion beam in a vacuum chamber; £dipositioning the at least one surface region of the medical device in the pnn.: ^ vacuum jiamber or irradiation _by_the first gas_ cluster ion beainj, pnn.; and 2.54 I'JS1? ιηοΉ -ΐινπ 1 0' " * (elirradialing the first deposited drug layer with the first gas cluster ion n"D 0 :mwH~ mw ,n"o beam so as to adhere a drug layer to the at least one surface region of the medical device such that a portion of the deposited drug substance is permitted to be released from the first adhered drug layer at a first expected rate; ( tl selectin an additional drug substance; (a) depositi ng the additional drug substance as an additional drug laver onto the most recently adhered dr m layer: ( 10 irradiating the additional drim layer with an additional gas cluster ion beam so as to adhere the additional drim layer onto the most recently 20 adhered drug layer such that a portion of the additional deposited drug substance is permitted to be released from the additional adhered drug layer at an additional expected rate: and (0 optional l y repeating steps ff) through (Ί) until a desired number o f additional adhered drug layers are formed.
2. The method o f claim 12 wherein some portion of as clusters comprising the first as cluster ion beam penetrate the first deposited drug layer and irradiate at least a portion of the at least one surface region of the medical device. i. The method _of claim 1 . wherein least one dhered drug layer comprises at least one carbonized substance formed of a portion the first deposited drug layer and including a f plural ity of interstices within which is disposed a non-carbonized portion o f the first deposited drug layer, a pl urality of the interstices being open at a surface of the - , carbonized su stance, so as to perm it the non-carbonized portion of the first deposited drug layer to be released at the expected rate. the at least one surface region comprises a plurality of spatially distinct regions of the surface of the medical device; 193283/2 pnn.i 37 * - - . J 9. The system of claim ,[9, where i ach^ncapsulating layer includes a carbonized or prim: the pnn s matrix densi lledjubstance, [ pnn . 38 20. The system of clai m ,20, wherein the encapsulating layer is adapted to improve a pnn_: it measure of biocompatibil ity of the member. pnn.; 3(> 5 \ 2 1 , he system o f dajm J_8, wherein the member is located on a surface of a medical pnn.i 3(i pfln_: <#>A drug delivery \ device. system, comprising:! a cohesive- mixtuic including a 22. The system of claim J_8, wherein the drug substance is selected from the group combination of a drug substance and a poly met or other material; 'ι consisting of anti-coagulants, antibiotics, anti-tumor substances, immune-suppressing a d¾ p ciirlioniicd ot dcnsitied intilt ix ',Ί agents, vasodilators, anti-proli fics, anti-thrombotic substances, anti-platelet substances, formed an outer sui face of the cohesive mixture, which cut lionized or detisified matrix is 1 0 ,'1 cholesterol reducing agents and combinations thereof. adapted to determine a release rate for the drug substance from tlic ',23, A medical devicejncl tiding the drug del i very system ol claim .1 8, cohesive mixture. ¾ 'l'he method of claim 9, wlictciti t!te step of providing a member includes forming n cohesive mixture of the drug substance and the polymer or other initlcriu! on it surface ol'a medical tlcvicc.it pnnj: pnna: <#>'t he method of claim 45. wherein the step of irradiating includes fbtmilig an encaps lating layct on at least an external surface of lite member, which encapsulating layer is adapted to control release of the dttig substance fiom the member, ΐ <#>The method of claim - 5, wherein lite encapsulating layer includes n plutality of openings at an outer surface of tile encapsulating layer so as to permit portions of the drug substance to be retained ('torn the member at a rate determined by the encapsulating layer. H <#>'i'he method of claim JS, wherein the encapsulating layer includes a cm lionized or detisified matrtx.1I <«>Tlic method of claim >14, wherein the step of pro iding a member includes 'he steps of providing a polymer clement and adhering u drug substance to an outer surface of the polymer
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2006
- 2006-10-17 US US11/550,069 patent/US7923055B2/en not_active Expired - Fee Related
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2007
- 2007-02-07 CA CA2638020A patent/CA2638020C/en not_active Expired - Fee Related
- 2007-02-07 JP JP2008553550A patent/JP5448458B2/en not_active Expired - Fee Related
- 2007-02-07 CA CA2916068A patent/CA2916068C/en not_active Expired - Fee Related
- 2007-02-07 WO PCT/US2007/061787 patent/WO2007092894A2/en active Application Filing
- 2007-02-07 EP EP07763398.0A patent/EP1986791B9/en not_active Not-in-force
- 2007-02-07 ES ES07763398.0T patent/ES2560865T3/en active Active
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2008
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2011
- 2011-03-07 US US13/041,525 patent/US8252418B2/en not_active Expired - Lifetime
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2012
- 2012-02-14 IL IL218121A patent/IL218121A0/en active IP Right Grant
- 2012-08-28 US US13/596,236 patent/US9226998B2/en not_active Expired - Fee Related
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WO2007092894A2 (en) | 2007-08-16 |
CA2638020A1 (en) | 2007-08-16 |
JP2009525787A (en) | 2009-07-16 |
US7923055B2 (en) | 2011-04-12 |
US9795719B2 (en) | 2017-10-24 |
EP1986791B9 (en) | 2017-05-31 |
CA2916068C (en) | 2020-04-28 |
US8252418B2 (en) | 2012-08-28 |
EP1986791B1 (en) | 2015-10-28 |
IL193283A0 (en) | 2009-08-03 |
US9226998B2 (en) | 2016-01-05 |
IL218121A0 (en) | 2012-03-29 |
EP1986791A4 (en) | 2011-09-28 |
US20160114083A1 (en) | 2016-04-28 |
US20110160845A1 (en) | 2011-06-30 |
US20070087034A1 (en) | 2007-04-19 |
US20120321707A1 (en) | 2012-12-20 |
CA2916068A1 (en) | 2007-08-16 |
JP5448458B2 (en) | 2014-03-19 |
WO2007092894A3 (en) | 2008-06-19 |
EP1986791A2 (en) | 2008-11-05 |
ES2560865T3 (en) | 2016-02-23 |
CA2638020C (en) | 2016-09-27 |
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